o:1699 Blocking STAT3/5 through direct or upstream kinase targeting in leukemic cutaneous T-cell lymphoma en Leukemic cutaneous T-cell lymphomas (L-CTCL) are lymphoproliferative disorders of skin-homing mature T-cells causing severe symptoms and high mortality through chronic inflammation, tissue destruction, and serious infections. Despite numerous genomic sequencing efforts, recurrent driver mutations have not been identified, but chromosomal losses and gains are frequent and dominant. We integrated genomic landscape analyses with innovative pharmacologic interference studies to identify key vulnerable nodes in L-CTCL. We detected copy number gains of loci containing the STAT3/5 oncogenes in 74% (n = 17/23) of L-CTCL, which correlated with the increased clonal T-cell count in the blood. Dual inhibition of STAT3/5 using small-molecule degraders and multi-kinase blockers abolished L-CTCL cell growth in vitro and ex vivo, whereby PAK kinase inhibition was specifically selective for L-CTCL patient cells carrying STAT3/5 gains. Importantly, the PAK inhibitor FRAx597 demonstrated encouraging anti-leukemic activity in vivo by inhibiting tumor growth and disease dissemination in intradermally xenografted mice. We conclude that STAT3/5 and PAK kinase interaction represents a new therapeutic node to be further explored in L-CTCL. Mycosis-Fungoides; Prognostic-Factors; Sezary-Syndrome; Expression; Apoptosis; Phosphorylation; Resistance; Mutations; Landscape; Growth 1552099 10.15252/emmm.202115200 2023-06-09T13:33:27.265Z 44 yes 46 Helena Sorger University of Veterinary Medicine, Vienna / Medical University Vienna / University of Vienna 0000-0002-3380-7770 Saptaswa Dey Medical University of Graz person 0000-0001-7532-7858 Pablo Augusto Vieyra-Garcia Medical University of Graz person 0000-0001-7101-9313 Daniel Pölöske University of Veterinary Medicine Vienna person Andrea R Teufelberger Medical University of Graz person 0000-0002-1142-949X Elvin D de Araujo University of Toronto person 0000-0003-0716-2830 Abootaleb Sedighi University of Toronto person Ricarda Graf Medical University of Graz person Benjamin Spiegl Medical University of Graz person 0000-0003-4497-6120 Isaac Lazzeri Medical University of Graz person Till Braun Cologne University person Ines Garces de Los Fayos Alonso University of Veterinary Medicine Vienna / Medical University Vienna person Michaela Schlederer Medical University of Vienna person Gerald Timelthaler Medical University of Vienna person Petra Kodajova University of Veterinary Medicine Vienna person 0000-0003-2746-7631 Christine Pirker Medical University of Vienna person Marta Surbek University of Veterinary Medicine Vienna person Michael Machtinger University of Veterinary Medicine Vienna person Thomas Graier Medical University of Graz person Isabella Perchthaler Medical University of Graz person Yi Pan Medical University of Graz person 0000-0001-6723-1370 Regina Fink-Puches Medical University of Graz person Lorenzo Cerroni Medical University of Graz person Jennifer Ober Medical University of Graz person Moritz Otte Cologne University person Jana D Albrecht University Hospital Mannheim person Gary Tin University of Toronto person Ayah Abdeldayem University of Toronto person Pimyupa Manaswiyoungkul University of Toronto person Olasunkanmi O. Olaoye University of Toronto person Martin L. Metzelder Medical University of Vienna person Anna Orlova University of Veterinary Medicine Vienna person 0000-0001-9262-7529 Walter Berger Medical University of Vienna person Marion Wobser University Hospital Wuerzburg person Jan P. Nicolay University Hospital Mannheim person Fiona André Medical University of Innsbruck person Van Anh Nguyen Medical University of Innsbruck person 0000-0003-2087-447X Heidi A Neubauer University of Veterinary Medicine Vienna person 0000-0001-7372-7786 Roman Fleck person Olaf Merkel Medical University of Vienna person Marco Herling Cologne University / University of Leipzig person Ellen Heitzer Medical University of Graz person Patrick T. Gunning University of Toronto person 0000-0003-0654-735X Lukas Kenner University of Veterinary Medicine Vienna person 0000-0003-0918-9463 Peter Wolf Medical University of Graz person 0000-0001-7777-9444 person application/pdf 1310550 https://phaidra.vetmeduni.ac.at/o:1699 no yes 16 70 1552253 EMBO Molecular Medicine 11 14 12 Wiley 2022